US3222370A - 4-phenalkyl-1-dialkyl-amino-alkylpiperidines - Google Patents

4-phenalkyl-1-dialkyl-amino-alkylpiperidines Download PDF

Info

Publication number
US3222370A
US3222370A US166694A US16669462A US3222370A US 3222370 A US3222370 A US 3222370A US 166694 A US166694 A US 166694A US 16669462 A US16669462 A US 16669462A US 3222370 A US3222370 A US 3222370A
Authority
US
United States
Prior art keywords
piperidine
benzyl
alkyl
grams
dimethylaminoethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US166694A
Other languages
English (en)
Inventor
Cavallito Chester John
Gray Allan Poe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NEISLER LAB Inc
NEISLER LABORATORIES Inc
Original Assignee
NEISLER LAB Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NEISLER LAB Inc filed Critical NEISLER LAB Inc
Priority to US166694A priority Critical patent/US3222370A/en
Priority to FR911255A priority patent/FR2239M/fr
Priority to GB1602/63A priority patent/GB970597A/en
Priority to DEJ23003A priority patent/DE1203267B/de
Application granted granted Critical
Publication of US3222370A publication Critical patent/US3222370A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • the inventionsought to be patented, in its composition aspect, is described as residing in the concept of a chemical compound having a molecular structure in which a phenylalkyl moiety is attached to the 4aposition of a 1- di-lower-alkylaminoalkyl) piperidine.
  • composition aspect of the invention in their free base form are high boiling' liquids or low melting, white crystalline solids; are substantially insoluble in water; are soluble in aqueous mineral or organic acids from which the acid salts may be obtained on evaporation of the Water; and, are soluble in polar and non-polar solvents such as lower aliphatic alcohols, chloroform, benzene and petroleum ether.
  • the tangible embodiments of the invention possess the inherent applied use characteristics of exerting an antiather-osclerotic effect and of potentiating the anti-hypertensive action of veratrum alkaloids.
  • composition aspects of the invention in their free base form, have the generalized structure Structure I wherein Alk represents an alkylene bridge containing one to three carbon atoms, Alk represents an alkylene bridge containing two to three carbon atoms, and R and R represent the same or different lower-alkyl groups, which can be joined to form a heterocyclic ring as in pyrrolidine, piperidine and morpholine.
  • alkyl or Alk refers to a straight or branched alkylene chain containing one to three carbon atoms; the terms alkyl or Alk as they appear in the terms (ii-lower alkylaminoalkyl or refer to an alkylene bridge, containing between 2 and 3 carbon atoms; and, the term lower-alkyl refers to straight or branched chain alkyl radicals having one to four carbon atoms, inclusive, among which are, for purposes of illustration but without limiting the generality "ice of the foregoing, methyl, ethyl, n-butyl, isopropyl and s-butyl.
  • the phenyl ring includes, as the full equivalent thereof, the unsubstituted phenyl radical and such radicals bearing on the ring, in place of a hydrogen atom or atoms, one or more simple substituents not adversely affecting the pharmacological properties of the above generalized structure, which includes, for purposes of illustration but without limiting the generality of the foregoing, halo, lower-alkyl, lower-alkoxy, methylenedioxy, amino, nitro, trihalomethyl, hydroxy, mercapto, loweralkylthio and other groups commonly used in the art as phenyl substituents.
  • the piperidine ring may have lower-alkyl substituents as well as the phenylalkyl substituent hereinbefore described. Such lower-alkyl derivatives are to be considered full equivalents of the unsubstituted compound of this invention.
  • phenylalkyl-l-(di-lower-alkylaminoalkyl)piperidines that are suitable examples of this invention include for purposes of illustration, but without limiting the generality of the foregoing, 4-p-chloro phenethyl-l- (,8 di-isopropylaminoethyl-piperidine, 4-(3,4- methylenedioxyphenethyl) l ('y pi-peridinopropyl)- piperidine, 4 (3,4,5 trimethoxphenethyl) 3-ethyl 1 (B diethylaminoethyl) piperidine, 4 (a phenyl propyl) 1 ('y pyrrolidinopropyl) piperidine, 4 (fiphenylpropyl) 1 (,8 diethylaminopropyl) piperidine, 4- a-phenylethyl- 1- fi-piperidinopropyl) piperidine.
  • phenylalkyl-di-lower alkylaminoalkyl-piperidines of the present invention in their free base form are most conveniently prepared by the reaction of 4-phenylalkylpiperidine with di-lower-alkylaminoalkyl ester of the type generally used as an alkylating agent in the presence of an acid acceptor such as sodium carbonate, potassium carbonate, etc.:
  • phenyl, Alk, Alk, R and R have the same meaning as in the above generalized structure I, and X a chlorine, bromine or iodine atom, or a sulfonate ester group.
  • the acid-addition salts of the compounds of the invention can be prepared in the conventional manner by reacting the free bases of the invention with the usual inorganic acids, which include, for purposes of illustration but without limiting the generality of the foregoing, hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric; or organic acids, which include, for purposes of illustration but without limiting the generality of the foregoing, acetic, tannic, citric, malic, ethanesulfonic, cyclohexylsulfamic, et cetera.
  • These salts are to be regarded as the full equivalents of the free bases, since they represent merely convenient forms in which to administer the compounds for the pharmacological purposes herein set forth.
  • the dihydrochloride salt of 4-benzyl-l-(fl-dimethylaminoethyl)--piperidine was prepared in the conventional manner and melted above 270 degrees centigrade.
  • the toxicity of the compounds was first evaluated in mice and then in dogs with favorable results. By standard pharmacological evaluation procedures, the antiatherosclerotic activity of the compounds was determined in rabbits. A further'property exhibited by our compositions is that they will significantly increase peripheral and coronary blood fiow and they potentiate the hypotensiveof the effective dosage range of 4-benzyl-l-( 8-d-imethylaminoethyl)-piperidine dihydrochloride. Pilot chronic toxicity studies, which were also conducted according to the usual, and well known procedures, were made and essentially the same results were observed.
  • the 4-benzyl-1-( lrdimethylaminoethyl)-piperidine dihydrochloride was orally administered in doses ranging from 5 mg. per kg. to 50 mg. per kg. At all doses, the degree of the atherosclerotic plaques was decreased 25-75% as compared to control animals.
  • 4-benzyl-1-(,B-dimethylaminoethyl)-piperidine dihydrochloride was administered to rabbits both prophylactically and after production of experimental atherosclerosis. In both experiments, the degree of the antherosclerotic plaques was reduced significantly.
  • the effective dosage of the compounds of this invention depends upon the severity, the stage, and the individual characteristics of each case. Generally a dosage range of 2 to 20 mg./ kg. of body weight per day constitutes the overall range, with a range of about 2 to 10 mg./kg. per day for the preferred compounds. Specifically, the following represents acceptable total daily doses for 4-phenethyl-1-(fl-dimethylaminoethyl) piperidine dihydrochloride, 0.5-10 mg. per kg.
  • Tablet formulation The following formulation provides for the manufacture of 1000 tablets:
  • Capsule formulation The following formulation provides for the manufacture of 1.000 capsules:
  • Parenteral formulatiom The following formulation provides for the manufacture of 1000 five cc. vials each containing 100 mg. of active ingredient per cc. as its hydrochloride salt:
  • the compounds of this invention are also useful as intermediate for the preparation of useful pharmaceutical compounds.
  • our copending application 593,058, filed June 22, 1956, describes the preparation of antihyptertensive compounds by the reaction of the compounds of this invention with lower-alkyl halides or methosulfates.
  • alkyl of the phenylalkyl group contains from 1 to 3 carbon atoms and alkyl of the aminoalkyl group contains from 2 to 3 carbon atoms.
  • composition of matter according to claim 1 in which phenylalkyl is benZyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US166694A 1962-01-16 1962-01-16 4-phenalkyl-1-dialkyl-amino-alkylpiperidines Expired - Lifetime US3222370A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US166694A US3222370A (en) 1962-01-16 1962-01-16 4-phenalkyl-1-dialkyl-amino-alkylpiperidines
FR911255A FR2239M (fr) 1962-01-16 1962-10-04 Médicaments a base de dialcoyl-aminoalcoyl-pipéridines.
GB1602/63A GB970597A (en) 1962-01-16 1963-01-14 Therapeutic compositions containing n-substituted 4-aralkyl-piperidines
DEJ23003A DE1203267B (de) 1962-01-16 1963-01-15 Verfahren zur Herstellung neuer N-(Dialkylaminoalkyl)-piperidine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US166694A US3222370A (en) 1962-01-16 1962-01-16 4-phenalkyl-1-dialkyl-amino-alkylpiperidines

Publications (1)

Publication Number Publication Date
US3222370A true US3222370A (en) 1965-12-07

Family

ID=22604336

Family Applications (1)

Application Number Title Priority Date Filing Date
US166694A Expired - Lifetime US3222370A (en) 1962-01-16 1962-01-16 4-phenalkyl-1-dialkyl-amino-alkylpiperidines

Country Status (4)

Country Link
US (1) US3222370A (fr)
DE (1) DE1203267B (fr)
FR (1) FR2239M (fr)
GB (1) GB970597A (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3381012A (en) * 1961-08-08 1968-04-30 Sterling Drug Inc Primary, secondary, and tertiary-(1-piperidyl)-lower-alkylamines
US3468892A (en) * 1965-03-19 1969-09-23 American Cyanamid Co Substituted piperidines
CN117587045A (zh) * 2024-01-16 2024-02-23 云南农业大学 一种藜芦胆固醇22（R）-羟化酶VnCYP90B27基因及应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2648133B1 (fr) * 1989-06-08 1992-02-21 Sanofi Sa Lauramides n-substitues, leur preparation et compositions les contenant

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2508332A (en) * 1945-03-09 1950-05-16 Ciba Pharm Prod Inc Beta-phenyl-beta-pyridyl and beta-phenyl-beta-piperidyl ethyl amines
US2687414A (en) * 1948-11-26 1954-08-24 Searle & Co Method for producing aromatic aminoalkyl amines
US2962500A (en) * 1957-08-12 1960-11-29 Ciba Pharm Prod Inc New alkyl-piperidines
US2986573A (en) * 1961-01-18 1961-05-30 Schering Corp Method for the treatment of hypertension
US2987442A (en) * 1959-02-17 1961-06-06 Smith Kline French Lab Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2508332A (en) * 1945-03-09 1950-05-16 Ciba Pharm Prod Inc Beta-phenyl-beta-pyridyl and beta-phenyl-beta-piperidyl ethyl amines
US2687414A (en) * 1948-11-26 1954-08-24 Searle & Co Method for producing aromatic aminoalkyl amines
US2962500A (en) * 1957-08-12 1960-11-29 Ciba Pharm Prod Inc New alkyl-piperidines
US2987442A (en) * 1959-02-17 1961-06-06 Smith Kline French Lab Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts
US2986573A (en) * 1961-01-18 1961-05-30 Schering Corp Method for the treatment of hypertension

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3381012A (en) * 1961-08-08 1968-04-30 Sterling Drug Inc Primary, secondary, and tertiary-(1-piperidyl)-lower-alkylamines
US3468892A (en) * 1965-03-19 1969-09-23 American Cyanamid Co Substituted piperidines
CN117587045A (zh) * 2024-01-16 2024-02-23 云南农业大学 一种藜芦胆固醇22（R）-羟化酶VnCYP90B27基因及应用
CN117587045B (zh) * 2024-01-16 2024-04-16 云南农业大学 一种藜芦胆固醇22（R）-羟化酶VnCYP90B27基因及应用

Also Published As

Publication number Publication date
DE1203267B (de) 1965-10-21
FR2239M (fr) 1963-12-30
GB970597A (en) 1964-09-23

Similar Documents

Publication Publication Date Title
US2986573A (en) Method for the treatment of hypertension
US4194045A (en) 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds
US3849561A (en) Anti-peptic ulcer substance from corydalis tubers
IE44639B1 (en) Oxadiazoloyl-substituted compounds having pharmacological activity
US4463208A (en) Treatment of gray matter edema
US3176040A (en) Novel 2, 2'-(ethylenediimino)-di-1-butanols
JPS6156227B2 (fr)
US3681346A (en) {60 -isomer of the decanoic acid ester of 10-{8 3,-(4-hydroxyethyl-1-piperazinyl)propylidene{9 -2-trifluoro-methyl thiaxanthene, acid addition salts thereof, method of use and compositions
US4307106A (en) Aminothiazoles
US3629266A (en) (phenyl piperidino alkyl)3 4-dihydrocarbostyrils
US2918407A (en) Anti-spasmodics specific for upper gastrointestinal pain and spasm
US2887481A (en) Heterocyclic amides
JPS58188879A (ja) シプロヘプタジン−３−カルボン酸及び構造的に関連した化合物のエステル
JPS63258415A (ja) Ｎ−置換２−シアンアジリジンを含有する免疫刺戟性薬剤
US4203989A (en) Anti-diarrheal diaryl-(1-azabicyclo(2.2.2)octan-2-yl)-alkanols and related compounds
US3627775A (en) 1-alkyl-1,2,5,6-tetrahydro-3-pyridylmethyl carboxylic
US3464990A (en) Barbituric acid derivatives substituted in the five position
US3163653A (en) -nhsoz-r
US3350407A (en) Sulfur containing pyrazole derivatives
US3725419A (en) Quinuclidylalkyl esters
US3432490A (en) 2-(beta-hexamethylene imino ethyl) cyclohexanone - 2 - carboxylic acid benzyl ester and salts thereof
EP0040947A1 (fr) Utilisation de guanidines pour la fabrication de medicaments antidiarrhéiques et compositions antidiarrhéiques contenant ces dernières
CA1078389A (fr) (2-azabicyclo (2.2.2) octan-2-yl) diphenylalcanones et leurs composes apparentes
US4001433A (en) Quaternary ammonium compounds useful as antifibrillatory agent
US3428653A (en) 3-indolylmethylguanidine